Clear cause-and-effect relationships are commonly established between genotype and the inherited risk of acquiring human and plant diseases and aberrant phenotypes. By contrast, few such cause-and-effect relationships are established linking a chromatin structure (that is, the epitype) with the transgenerational risk of acquiring a disease or abnormal phenotype. It is not entirely clear how epitypes are inherited from parent to offspring as populations evolve, even though epigenetics is proposed to be fundamental to evolution and the likelihood of acquiring many diseases. This article explores the hypothesis that, for transgenerationally inherited chromatin structures, “genotype predisposes epitype”, and that epitype functions as a modifier of gene expression within the classical central dogma of molecular biology. Evidence for the causal contribution of genotype to inherited epitypes and epigenetic risk comes primarily from two different kinds of studies discussed herein. The first and direct method of research proceeds by the examination of the transgenerational inheritance of epitype and the penetrance of phenotype among genetically related individuals. The second approach identifies epitypes that are duplicated (as DNA sequences are duplicated) and evolutionarily conserved among repeated patterns in the DNA sequence. The body of this article summarizes particularly robust examples of these studies from humans, mice, Arabidopsis, and other organisms. The bulk of the data from both areas of research support the hypothesis that genotypes predispose the likelihood of displaying various epitypes, but for only a few classes of epitype. This analysis suggests that renewed efforts are needed in identifying polymorphic DNA sequences that determine variable nucleosome positioning and DNA methylation as the primary cause of inherited epigenome-induced pathologies. By contrast, there is very little evidence that DNA sequence directly determines the inherited positioning of numerous and diverse post-translational modifications of histone side chains within nucleosomes. We discuss the medical and scientific implications of these observations on future research and on the development of solutions to epigenetically induced disorders.
BackgroundThe actin cytoskeleton is involved in an array of integral structural and developmental processes throughout the cell. One of actin’s best-studied binding partners is the small ubiquitously expressed protein, profilin. Arabidopsis thaliana is known to encode a family of five profilin sequence variants: three vegetative (also constitutive) profilins that are predominantly expressed in all vegetative tissues and ovules, and two reproductive profilins that are specifically expressed in pollen. This paper analyzes the roles of the three vegetative profilin members, PRF1, PRF2, and PRF3, in plant cell and organ development.ResultsUsing a collection of knockout or severe knockdown T-DNA single mutants, we found that defects in each of the three variants gave rise to specific developmental deficiencies. Plants lacking PRF1 or PRF2 had defects in rosette leaf morphology and inflorescence stature, while those lacking PRF3 led to plants with slightly elongated petioles. To further examine these effects, double mutants and double and triple gene-silenced RNAi epialleles were created. These plants displayed significantly compounded developmental defects, as well as distinct lateral root growth morphological phenotypes.ConclusionThese results suggest that having at least one vegetative profilin gene is essential to viability. Evidence is presented that combinations of independent function, quantitative genetic effects, and functional redundancy have preserved the three vegetative profilin genes in the Arabidopsis lineage.Electronic supplementary materialThe online version of this article (doi:10.1186/s12870-015-0551-0) contains supplementary material, which is available to authorized users.
While a clear cause‐and‐effect relationship is well established between genotype and inheritance of risk factors for human disease, the link between cis‐linked chromatin structures (epitypes) and the risk of acquiring disease is much less clear. This is in part due to the fact that neither the rules nor the rates governing the evolution of epitypes are well understood. There are two ways to establish that particular epitypes have the potential to contribute to the inherited risk of disease. Traditionally, the transgenerational inheritance of risk factors and epitypes in related individuals are measured directly. In addition, risk factors that are transgenerationally inherited may be identified by analyzing the conservation of epitypes after gene duplication. Using these data we've established a hierarchy of epigenetic controls based on their potential to contribute to risk. DNA sequence changes would reside at the pinnacle of the risk pyramid evolving in parallel with epigenetic risk. Below would be other transgenerationally inherited properties like nucleosome position and cytosine methylation. Finally, histone modifications appear to be the least likely to be transgenerationally inherited, and hence, therefore are at the bottom of the pyramid. One outcome of this research is establishing a clear distinction between inherited epigenetic risk and somatically inherited epigenetic factors contributing to organ and cell development. This study is funded by NIH research grant GM‐36397 and training grant GM‐07103.
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